Beltran_subbed.qxp 13/7/09 12:31 Page 40
Lung Cancer
Respiratory Homeostasis and Exploitation of the
Immune System for Lung Cancer Vaccines
Adam Yagui-Beltrán, MD,
1
Lisa M Coussens, PhD
2
and David M Jablons, MD
3
1. Post-doctoral Fellow; 2. Professor of Pathology; 3. Ada Distinguished Professor of Thoracic Oncology and Chief of General Thoracic Surgery,
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
Abstract
Lung cancer is the leading cause of all cancer deaths in the US. The international scientific and clinical community has made significant
advances toward understanding specific molecular mechanisms underlying lung carcinogenesis; however, despite these insights and advances
in surgery and chemoradiotherapy, the prognosis for non-small-cell lung cancer (NSCLC) remains poor. Nonetheless, significant effort is being
focused on advancing translational research evaluating the efficacy of novel targeted therapeutic strategies for lung cancer. Illustrative
examples of this include antagonists of the epidermal growth factor receptor (EGFR), tyrosine kinase inhibitors (TKIs) such as gefitinib and
erlotinib, and a diverse assortment of anti-angiogenic compounds targeting growth factors and/or their receptors that regulate tumor-
associated angiogenic programs. In addition, with the increased awareness of the significant role chronically activated leukocytes play as
potentiators of solid-tumor development, the role of innate and adaptive immune cells as regulators of lung carcinogenesis is being examined.
While some of these studies are examining how novel therapeutic strategies may enhance the efficacy of lung cancer vaccines, others are
evaluating the intrinsic characteristics of the immune response to lung cancer in order to identify rate-limiting molecular and/or cellular
programs to target with novel anticancer therapeutics. In this article, we explore important aspects of the immune system and its role in
regulating normal respiratory homeostasis compared with the immune response accompanying development of lung cancer. These hallmarks
are then discussed in the context of recent efforts to develop lung cancer vaccines, where we have highlighted important concepts that must
be taken into consideration for future development of novel therapeutic strategies and clinical trials assessing their efficacy.
Keywords
Non-small-cell lung cancer, immune system, immunotherapy, immunomodulation, leukocytes, lung cancer vaccines, clinical trials
Disclosure and Funding: Supported by The Kazan Foundation and Research Project Grant Program (R01) grants (CA093708 and CA13566) from the National Institutes of Health/
National Cancer Institute (NIH/NCI). Lisa M Coussens, PhD, is supported by R01 grants from the NIH/NCI (CA130980, CA13566) and a Breast Cancer Research Program (BCRP) Era of
Hope Scholar Award (W81XWH-06-1-0416).
Received: February 2, 2009 Accepted: April 13, 2009
Correspondence: David M Jablons, MD, Professor and Chief, Thoracic Surgery, Ada Endowed Chair and Program Leader, Thoracic Oncology, Department of Surgery and UCSF Helen
Diller Family Comprehensive Cancer Center, 1600 Divisadero St, Box 1724, San Francisco, CA 94143-1724. E:
david.jablons@ucsfmedctr.org
Lung cancer is the main cause of cancer deaths for both men and affecting an older male population. This social prejudice led to
women in the US and worldwide. In the US, there were approximately stagnation for many decades in understanding the molecular and
232,270 new cases diagnosed and 166,280 deaths due to this disease histopathological basis of lung cancer. However, the staggering lung
by the end of 2008.
1
Non-small-cell cancer (NSCLC) accounts for cancer mortality statistics at a global level have fueled an attitude
approximately 80% of all cases of lung cancer, the rest being small- shift and increased awareness that favors education and basic and
cell lung cancer (SCLC). Unfortunately, despite efforts by scientists translational lung cancer research dedicated toward the development
and clinicians aimed at improving survival, delayed diagnosis with of efficacious diagnostic and therapeutic tools. To this end, molecular
subsequent late-stage disease and high rates of recurrence even in genetic studies have recently revealed that histopathologically
patients with early-stage disease ultimately results in suboptimal distinct lung cancers contain an array of genetic and epigenetic
prognosis and decreased disease-free survival. In fact, overall five- anomalies that account for their diverse nature.
3
Many of these
year survival rates in lung cancer patients have only modestly abnormalities are also found in histologically normal or pre-neoplastic
improved over the last few decades, with the current five-year adjacent lung epithelial tissue, thus indicating a multistep process of
survival rate being around 15% in the US and much lower in carcinogenesis encompassing the progressive accumulation of
developing countries.
2
Until recently, limited federal resources were genetic and epigenetic changes that occur concurrent to tobacco
dedicated to the study of lung cancer largely due to it being a disease smoking, and underlies the initiation, promotion, and progression
resulting from a lifestyle choice (tobacco smoking) and it typically stages of lung carcinogenesis.
4
Clinical translation of these insights
40 © TOUCH BRIEFINGS 2009
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100